The conditions grouped under the term “central nervous system disorder” constitute an area of continuing medical need. Such conditions include those disorders associated with neuropathic pain, inflammatory pain, inflammation-related pain or epilepsy.
Sodium channels have been suggested to play a role in (and sodium channel blockers to be useful in treating) many disorders of the central nervous system (Madge, D., Sodium Channels: Recent Developments and Therapeutic Potential, Annual Reports in Medicinal Chemistry, 1998, 33, 51-60, 56). The majority of the compounds studied to date show some potential in more than one of these disorders; very few compounds with selective anticonvulsant, analgesic or neuroprotective activity have been identified (Madge, D., p 56).
In the past few years a much better understanding of sodium channels and drugs interacting with them has been developed (Anger, T., Madge, D., Mulla M. and Riddall, D., Medicinal Chemistry of Neuronal Voltage-Gated Sodium Channel Blockers, Journal of Medicinal Chemistry, 2001, 44(2), 115-137). It has become clear that a number of drugs having an unknown mechanism of action actually act by modulating sodium channel conductance, including local anesthetics, class I antiarrhythmics and anticonvulsants (Anger, T., et al., p 123). Neuronal sodium channel blockers have found application with their use in the treatment of epilepsy (phenytoin and carbamazepine, long used as anticonvulsants but without a clear understanding of their mechanism of action), neuroprotection (as a result of ischemic stroke and other brain trauma), preventing neurodegeneration (such as in the treatment of amyotrophic lateral sclerosis by, primarily, sodium channel blockage) and in reducing neuropathic pain (as a result of trigeminal neuralgia, diabetic neuropathy, post-herpetic neuralgia, neuroma pain and phantom limb syndrome) (Anger, T., et al., pp 124, 126, 129).
Neuropathic pain and other chronic and debilitating condition-associated pain syndromes are all associated with changes in neuronal excitability (Brau M. E., et al, Effect of drugs used for neuropathic pain management on tetrodotoxin-resistant Na(+) currents in rat sensory neurons, Anesthesiology, 2001, January, 94(1), 137-44; Siddall P. J. and Loeser J. D., Pain following spinal cord injury, Spinal Cord, 2001, February, 39(2), 63-73; Kontinen V. K., et al, Electrophysiologic evidence for increased endogenous gabanergic but not glycinergic inhibitory tone in the rat spinal nerve ligation model of neuropathy, Anesthesiology, 2001, February, 94(2), 333-9).
Various anti-epileptic drugs (AEDs) that stabilize neuronal excitability are effective in neuropathic pain (Johannessen C. U., Mechanisms of action of valproate: a commentatory, Neurochem. Int., 2000, August-September, 37(2-3), 103-110 and Magnus L., Nonepileptic uses of gabapentin, Epilepsia, 1999, 40 Suppl 6, S66-72; Nadin Attal, et al., Effects of Gabapentin on the Different Components of Peripheral and Central Neuropathic Pain Syndromes: A Pilot Study, Fr. Eur. Neurol. 1998, 40(4), 191-200.
In particular, neuropathic pain is defined as pain caused by aberrant somatosensory processing in the peripheral or central nervous system and includes neuropathic pain resulting from chronic or debilitating conditions (such as painful diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain, multiple sclerosis-associated pain, neuropathies-associated pain (such as in idiopathic or post-traumatic neuropathy and mononeuritis), HIV-associated neuropathic pain, cancer-associated neuropathic pain, carpal tunnel-associated neuropathic pain, spinal cord injury-associated pain, complex regional pain syndrome, fibromyalgia-associated neuropathic pain, lumbar and cervical pain, reflex sympathic dystrophy, phantom limb syndrome and other chronic and debilitating condition-associated pain syndromes), sympathetically maintained pain or cluster and migraine headache-associated pain; pain associated with cancer, fibromyalgia, back disorders or migraine and chronic headache, adiposis dolorosa and burn pain, central pain conditions following stroke, thalamic lesions or multiple sclerosis or pain resulting from damage to the peripheral or central nervous system (after amputation, paraplegia, herpes or as a result of diabetic polyneuropathy).
An increase in sodium channel expression or activity is observed in several animal models of inflammatory pain. Expression of α-SNS mRNA and tetrodotoxin-resistant sodium current in small DRG neurons increased following injection of carrageenan into the plantar surface of the rat hindpaw (Tanaka M., NeuroReport, 1998, 9, 967-972). Similarly, the induction of chronic inflammation with the injection of Complete Freund's Adjuvant was followed by the development of inflammatory thermal hypersensitivity and increased sodium channel staining (Gould H. J., et al., Brain Res., 1998, 802 (1), 69-74; Gould H. J., et al., Brain Res., 1999, 824, 296-299). Antisense (but not sense or missense) to the PN3 sodium channel prevented the development of mechanical flexion reflex hyperalgesia following the administration of the inflammatory agent PGE2 (Khasar S. G., et al., Neurosci. Lrs., 1998, 256, 17-20).
Patent references describe compounds as sodium channel modulators or antagonists for use in treating or modulating central nervous system disorders in a number of in vitro and in vivo models.
U.S. Pat. No. 6,288,278 describes 3-amino-3-arylpropan-1-ol derivatives as sodium channel blockers in a BTX-binding assay (S. W. Postma & W. A. Catterall, Mol. Pharmacol., 1984 25, 219-227) and methods for use as local anesthetic, antiarrhythmic, antiemetic and nootropic (neurotropic) agents and as agents for the treatment/therapy of cardiovascular diseases, urinary incontinence, diarrhea, pruritus, alcohol or drug dependency and inflammation.
U.S. Pat. No. 6,288,123 describes disubstituted guanidine compounds as modulators or inhibitors for release of neurotransmitters such as glutamate from ischemic neuronal cells by blocking presynaptic calcium and/or sodium channels in an inhibition of glutamate release assay, in an inhibition of 45Ca uptake through presynaptic calcium channels assay, in an inhibition of 45Ca uptake through L-type (dihydropyridine-sensitive) calcium channels assay, in an inhibition of [14C]-guanidinium uptake through Type II neuronal voltage-activated sodium channels assay, in an in vivo anticonvulsant/audiogenic seizures D6A/2 mouse model and methods for use in the treatment and/or prophylaxis of neurological conditions such as epilepsy, neurodegenerative conditions and diseases (such as Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome, Korsakoff's disease, olivopontocerebellar atrophy, HIV-induced dementia and blindness or multi-infarct dementia) and nerve cell death (as a result of hypoxia, hypoglycemia, brain or spinal chord ischemia, brain or spinal chord trauma or global cerebral ischemia (as a result of stroke, heart attack, drowning or carbon monoxide poisoning)); for use in the treatment of hypertension, cardiac arrhythmias or angina pectoris, endocrine disorders (such as acromegaly and diabetes insipidus) and chronic pain (including use as a local anesthetic); and, for use in the treatment of diseases in which the pathophysiology of the disorder involves excessive or otherwise inappropriate (e.g., hypersecretory) cellular secretion (e.g., secretion of an endogenous substance such as a catecholamine, a hormone or a growth factor).
U.S. Pat. No. 6,281,211 describes semicarbazide compounds as sodium channel blockers in a dissociated hippocampal neuron electrophysiological assay, in a neuronal voltage-dependent in a rat forebrain membrane assay, in HEK-293 cells stably expressing hSkM 1 sodium channels, in a [3H]BTX-B assay and in a mouse maximal electroshock-induced seizure (MES) model and methods for treating, preventing or ameliorating neuronal loss (associated with stroke, global and focal ischemia, CNS trauma, hypoglycemia, surgery and spinal cord trauma), for the treatment or prevention of neurodegenerative conditions (such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, anxiety, convulsions, glaucoma, migraine headache and muscle spasm), as antimanic depressants, as local anesthetics, as antiarrhythmics, as anticonvulsants, as agents for the treatment or prevention of diabetic neuropathy and for the treatment of pain (acute, chronic and surgical pain, neuropathic pain and migraine headache).
U.S. Pat. No. 6,265,405 describes 5-amino triazine derivatives as sodium channel blockers in a whole-cell (recombinant human brain type IIA Na+ channel expressed in Chinese hamster ovary cells) voltage-clamp assay, as anticonvulsants in a rat MES model and a mouse pentylenetetrazol infusion test, as agents for treating acute hyperalgesia and inflammation in a rat carrageenan paw model, as a neuroprotective agent in a MPTP-induced neurotoxicity model for Parkinson's disease and methods for treating epilepsy (including simple partial seizures, complex partial seizures, secondary generalised seizures and generalized seizures (further including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures), bipolar disorder (alternatively known as manic depression; including Type I or II) and unipolar depression; for treating or preventing acute pain (musculoskeletal, post operative and surgical pain), chronic pain (inflammatory pain (from rheumatoid arthritis and osteoarthritis), neuropathic pain (from post herpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and pain associated with cancer, fibromyalgia and migraine associated pain; for treating tinnitus, functional bowel disorders (non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome) and neurodegenerative diseases (Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, muscular sclerosis, macular degeneration and glaucoma), for neuroprotection (treating neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury and spinal cord injury) and for preventing or reducing dependence/tolerance/reverse tolerance to a dependence-inducing agent (such as opioids, CNS depressants, psychostimulants and nicotine).
U.S. Pat. No. 6,262,078 describes phenoxymethyl piperidine derivatives as sodium channel blockers in an in vitro rat vagus nerve assay (Kourtney and Stricharz, Local Anesthetics, Springer-Verlag, New York, 1987) and as agents for the treatment of neuropathic pain in an in vivo rat mechanical allodynia model (Kim and Chung, Pain, 1992, 50:355-363), in an in vivo rat acute and chronic cold allodynia, unilateral mononeuropathy, Chronic Constriction Injury model (Bennet and Xie, Pain, 1988, 33:87-107), in an in vivo rat mechanical hyperalgesia model (Bennet and Xie, Pain, 1988, 33:87-107) and in an in vivo rat thermal hyperalgesia model and methods for treating peripheral neuropathies (trigeminal neuralgia, postherpetic neuralgia, diabetic neuropathy, glossopharyngeal neuralgia, lumbar and cervical radiculopathies, reflex sympathetic dystrophy and causalgia), neuropathy secondary to metastatic infiltration, adiposis dolorosa and burn pain and central pain conditions following stroke, thalamic lesions and multiple sclerosis.
U.S. Pat. No. 6,255,307 describes a class of phenyl pyrazine derivatives as sodium channel blockers and methods for treating epilepsy (including simple partial seizures, complex partial seizures, secondary generalised seizures and generalized seizures (further including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures), bipolar disorder (alternatively known as manic depression; including Type I or II) and unipolar depression; for treating or preventing acute pain (musculoskeletal, post operative and surgical pain), chronic pain (inflammatory pain (from rheumatoid arthritis and osteoarthritis), neuropathic pain (from post herpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and pain associated with cancer, fibromyalgia and migraine associated pain; for treating tinnitus, functional bowel disorders (non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome) and neurodegenerative diseases (Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, muscular sclerosis, macular degeneration and glaucoma), for neuroprotection (treating neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury and spinal cord injury) and for preventing or reducing dependence/tolerance/reverse tolerance to a dependence-inducing agent (such as opioids, CNS depressants, psychostimulants and nicotine).
U.S. Pat. No. 6,169,116 describes tetrahydro-naphthalenamines as sodium channel blockers in a rat hippocampal veratridine induced glutamate inhibition assay (modification of M. J. Leach et al., Epilepsia, 1986, 27, 490-497 and Stroke, 1993, 24, 1063-1067 using exogenous glutamate) and in a veratridine binding assay (J. B. Brown, Journal of Neuroscience, 1986, 6, 2064-2070), as agents for reducing ischemia-induced neuronal damage and ensuing symptoms in a rat middle cerebral artery (MCA) occlusion model (A. Tamura et al., J. Cereb. Blood Flow Metabol., 1981, 1, 53-60; A. Sauter and M. Rudin, Stroke, 1986, 17, 1228-1234) and methods for the treatment of any clinical condition involving a component of cerebral anoxia, hypoxia or ischemia (ischemic damage to grey and white matter) as a result of stroke, subarachnoid hemorrhage, brain and spinal cord injury/trauma, high intracranial pressure, multi-infarct dementia or vascular dementia, as the result of any surgical procedure potentially associated with cerebral anoxia, hypoxia and/or ischemia (cardiac bypass, operations on extracerebral vessels), as the result of any pathology, disorder or clinical condition involving glutamate release in their etiology (including psychiatric disorders (such as schizophrenia, depression, anxiety, panic attacks, attention deficit and cognitive disorders or social withdrawal), hormonal conditions (such as excess GH (as in diabetes mellitus, angiopathy or acromegaly) or LH (as in prostate hypertrophy, menopausal syndrome] secretion or corticosterone secretion in stress)), metabolic induced brain damage (hypolycemia, non-ketotic hyperglycinaemia (glycine encephalopathy), sulphite oxidase deficiency or hepatic encephalopathy associated with liver failure), emesis, spasticity, tinnitus, pain (as a result of cancer or arthritis) and drug abuse and withdrawal (as a result of the use of ethanol, opiate (including synthetics with opiate-like effects), cocaine, amphetamine, barbiturate and other sedatives and benzodiazepines)), as the result of any pathology involving neuronal damage (including neurodegenerative disorders such as Alzheimer's, Huntington's or Parkinson's diseases, virus induced neurodegeneration (including HIV), ALS, supra-nuclear palsy, olivoponto-cerebellar atrophy (OPCA) and the actions of environmental, exogenous neurotoxins.
U.S. Pat. No. 6,172,085 describes cyclic ether compounds as sodium channel blockers in a rat cerebral cortex fraction binding model and methods for treating central nervous system (CNS) diseases and disorders such as CNS ischemia, CNS trauma (brain trauma, spinal cord injury or whiplash injury), epilepsy, neurodegenerative diseases (ALS, Alzheimer's disease, Huntington's chorea, Parkinson's disease or diabetic neuropathy), vascular dementia (multi-infarct dementia or Binswanger's disease), manic-depressive psychosis, depression, schizophrenia, chronic pain, trigeminal neuralgia, migraine and cerebral edema.
U.S. Pat. No. 6,051,583 describes substituted 2,3,3a,4,9,9a-hexahydro-8-hydroxy-1H-benz[f]indole derivatives as sodium channel blockers in a BTX-binding assay (S. W. Postma & W. A. Catterall, Mol. Pharmacol., 1984 25, 219-227) and in patch-clamp experiments (W. A. Catterall, Trends Pharmacol. Sci., 1987, 8, 57-65), as anticonvulsants in a mouse MES model (M. A. Rogawski and R. J. Porter, Pharmacol. Rev., 1990, 42, 223-286), as neuroprotective agents in a veratridine induced glutamate inhibition assay (S. Villauneva, P. Frenz, Y. Dragnic and F. Orrego, Brain Res., 1988, 461, 377-380) and in a rat-MCAO-model (U. Pschorn and A. J. Carter, J. Stroke Cerebrovascular Diseases, 1996, 6, 93-99) and methods for treating neurodegenerative diseases (resulting from arrhythmia, spasm and cardiac and cerebral ischaemia, hypoglycaemia, hypoxia, anoxia, brain trauma, cerebral oedema, stroke and perinatal asphyxia) and those associated with epilepsy, amylotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, disorders of heart rhythm, angina pectoris, pain (nociceptor pain, neuropathic pain, pain resulting from damage to the peripheral or central nervous system (after amputation, paraplegia, herpes or in diabetic polyneuropathy) and pain caused by functional disorders (migraine and back pain)).
PCT application WO 01/23570 describes voltage-gated sodium channel β1A subunit splice variant nucleic acids and proteins as useful in the treatment of neuropathic pain. PCT application WO 00/61231 describes the use of sodium channel antagonists for treating diseases mediated or exacerbated by sensory neuronal apoptosis: in particular, pain states (such as chronic pain) following nerve insult associated with tissue damage (due to injury or infection), neurodegenerative diseases (such as multiple sclerosis and Parkinson's disease) and inflammation. PCT application WO 00/02865 describes the use of pharmaceutical agents in blocking the activity of voltage-sensitive sodium channels for treating neuronal damage resulting from acute events such as ischemia or hypoxia or from neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or lateral amyotrophic sclerosis.